ABSTRACT When Cryptococcus is manifested as cryptococcal meningitis (CM), it creates a large burden of mortality and morbidity to the patient and is very difficult for the clinician to treat. There are now an estimated 2600-7800 US cases and 400,000 cases of CM worldwide annually, with estimated mortality of 15-50% per year. CM is caused when Cryptococcus neoformans, a basidiomycete fungal pathogen, invades the central nervous system (CNS). It is seen most commonly in immunocompromised patients, such as those with HIV or post organ-transplant. Current treatments include anti-fungal agents that have limited effectiveness in penetrating the CNS and various systemic side effects. Early reduction in pathogen burden is the best predictor of reduced morbidity and mortality. Minnetronix, a medical device development and manufacturing company, proposes this Phase II STTR in collaboration with experts from the Infectious Diseases and Neurosurgery Departments at Duke University. Phase I demonstrated the dramatic results of Neurapheresis, a cerebrospinal fluid (CSF) processing platform, with the ability for targeted delivery of Amphotericin B (AMB) along with rapid clearance of organisms both in vitro and in vivo, in a rabbit CM model. Phase II will optimize and validate a tailored human system to deliver the first-ever fungicidal platform. It will allow for delivery and circulation of AMB intrathecally, control of drug concentration and toxicity, rapid removal of C. neoformans and downstream mediators from the CSF, sampling of CSF to follow CFU reduction, and drainage of CSF to normalize ICP. Specific Aim 1 will understand and optimize the delivery, circulation, and dosing of AMB via the Neurapheresis system in a cranial/spinal model and develop a PK/PD model. Specific Aim 2 will demonstrate the safety and efficacy of Neurapheresis filtration and AMB circulation in a pivotal rabbit CM model study. Specific Aim 3 will complete development of the validated Neurapheresis system for intrathecal AMB delivery and targeted removal of organism from the CSF. Neurapheresis is an innovative, new therapeutic option that provides direct access to the CSF and allows for delivery and active circulation of intrathecal drug, combined with targeted pathogen removal through filtering. This treatment is complementary and does not replace standard interventions with systemic, intravenous antifungal regimens. Successful completion of this Phase II STTR will provide Minnetronix with the ability to complete development of a GLP-quality system for the treatment of CM. Concurrent regulatory and clinical study planning will be conducted to prepare for an investigational device exemption (IDE) application at the end of Phase II. The long-term goal of the project is to develop a novel fungicidal approach that rapidly eliminates the CSF fungal burden and translates to reduced morbidity and mortality for CM patients worldwide.